Lysosomal storage disorders (LSDs) include over 50 different diseases with a wide range of clinical phenotypes and a combined incidence of 1 in 7000 live births. LSDs are each caused by a genetic deficiency of lysosomal enzymes, resulting in the accumulation of unprocessed glycosaminoglycans (GAG) and progressive tissue damage. Enzyme replacement therapy (ERT) provides an effective treatment for many LSDs and is approved by the US Food and Drug Administration for treatment of mucopolysaccharidosis (MPS) type I, II, IV, type I Gaucher, and Fabry diseases. ERT involves intravenous injection of therapeutic enzymes to replenish absent or defective enzymes and thus clear accumulating metabolites.
Administration of recombinant enzymes can induce immune responses in patients that lack or possess truncated endogenous enzymes. In fact, antibodies against therapeutic enzymes are found in the serum of ERT patients with frequencies ranging from 15% for Gaucher, 55-80% for Fabry, 91% for MPS I, 97% for MPS IV, and 100% for Pompe disease. There is increasing evidence that antibody responses in patients can hinder ERT efficacy. For example, in Pompe disease, there are clear relationships between protein levels, antibody responses, and therapeutic outcomes. Patients with complete absence of acid alpha-glucosidase were found to have high antibody titers against this enzyme and show inhibition of enzyme uptake and activity during ERT. Other studies also suggest similar results in Fabry and Pompe diseases. In a MPS I animal model, it was also reported that α-L-iduronidase specific antibodies reduce ERT therapeutic efficacy. Induction of immune-tolerance by treatment of patients with immunosuppressive drugs was shown to increase tissue enzyme levels and reduce GAG levels in said patients. Antibody mediated inhibition of enzyme uptake in MPS I patients also strongly correlated to poorer biomarker responses which may suggest an important role in clinical outcomes. Life-threatening anaphylactic reactions have also occurred in patients receiving a recombinant human alpha-iduronidase, laronidase. These studies highlight the importance of maintaining minimal immune responses against recombinant enzymes in ERT clinical use.
LSDs are usually heterogeneous in individual patients and thus a universal deimmunization method such as removing immunogenic epitopes of the therapeutic protein is difficult to achieve. Current strategies to overcome the antibody responses to recombinant enzymes are largely focused on inducing immune tolerance. However, this may be harmful to patients because the regimen is usually coupled with high doses of immunosuppressive drugs. Increased risk of infection and malignancy are also of concern.